Inflammation contributes to pathogenesis of inflammatory diseases, or diseases associated with inflammation, such as autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and autoimmune hepatitis; degenerative diseases with an inflammatory component such as osteoarthritis (OA), Alzheimer's disease (AD), and macular degeneration; chronic infections such as HIV; metabolic diseases with an inflammatory component such as type II diabetes, metabolic syndrome, and atherosclerosis; and malignant diseases including cancers. Aminoquinolines including hydroxychloroquine (HCQ) are used as anti-inflammatory agents to treat certain inflammatory diseases.
Aminoquinolines are derivatives of quinoline that are most notable for their roles as antimalarial drugs, but they also possess anti-inflammatory properties. Examples of drugs of the aminoquinoline class include, but are not limited to, 4-aminoquinolines, such as amodiaquine, hydroxychloroquine (HCQ), chloroquine; and 8-aminoquinolines, such as primaquine and pamaquine. 4-Aminoquinoline is a form of aminoquinoline with the amino group at the 4-position of the quinoline. A variety of derivatives of 4-aminoquinoline are antimalarial agents, and examples include amodiaquine, chloroquine, and HCQ.
The 4-aminoquinoline HCQ was initially developed as hydroxychloroquine sulfate (HCQ sulfate) for use as an antimalarial drug. Hydroxychloroquine sulfate is sold under the trade names Plaquenil™, Axemal™ (in India), Dolquine™, and Quensyl™, and is also widely used to reduce inflammation in the treatment of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's Syndrome, and porphyria cutanea tarda. HCQ differs from chloroquine by having a hydroxyl group at the end of the side chain: The N-ethyl substituent is beta-hydroxylated. It is available for oral administration as hydroxychloroquine sulfate (Plaquenil), of which 200 mg contains 155 mg hydroxychloroquine base in chiral form. In addition to 155 mg of hydroxychloroquine base, each Plaquenil tablet contains the following inactive ingredients: sulfate (SO4), anhydrous lactose, croscarmellose sodium, glyceryl triacetate, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, povidone, sodium lauryl sulfate and titanium dioxide. Hydroxychloroquine sulfate has similar pharmacokinetics to chloroquine phosphate, being quickly absorbed by the gastrointestinal tract and eliminated by the kidney. Cytochrome P450 enzymes (CYP 2D6, 2C8, 3A4, and 3A5) N-desethylate HCQ to N-desethylhydroxychloroquine (Kalia et al. (2007) Dermatologic Therapy 20 (4): 160-174).
The most common adverse effects of HCQ therapy are mild nausea and occasional stomach cramps with mild diarrhea. The most serious adverse effects affect the eye. One of the most serious side effects of chronic HCQ use is ocular and retinal toxicity (Flach. Transactions of the American Ophthalmological Society, 2007, 105: 191-4; discussion 195-7).
Prolonged use of HCQ, chloroquine, or other aminoquinolines is associated with the development of eye toxicity (Marmor et al. Arthritis Care Res. 2010; 62(6):775-84; Levy et al, Incidence of hydroxychloroquine retinopathy in 1,207 patients in a large multicenter outpatient practice. Arthritis Rheumatism 1997, 40(8):1482-6; Mavrikakis et al, The incidence of irreversible retinal toxicity in patients treated with hydroxychloroquine: a reappraisal. Opthalmology, 2003, 110(7):1321-6). The incidence of such toxicity increases markedly with the duration of therapy, with ophthalmoscopically visualized loss of retinal pigmented epithelium in approximately 0.5-1% of HCQ sulfate treated humans after 5 years; and approximately 2% of HCQ sulfate treated humans after 10-15 years. Considerably higher rates of toxicity are observed with chloroquine. Notably, despite the observed rates of retinal toxicity, total rates of physician discontinuation of HCQ for earlier eye problems (including asymptomatic changes noted on ophthalmologic examination) approach 7% of HCQ sulfate treated patients over 5 years (Marmor et al. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic lupus erythematosus, Arthritis Care Res. 2010; 62(6):775-84).
Toxicity due to HCQ may occur in two distinct areas of the eye: the cornea and the macula. The cornea may become affected (relatively commonly) by an innocuous vortex keratopathy that is characterized by whorl-like corneal epithelial deposits. Changes to the macula (a component of the retina) are more serious and are related to dosage and duration of HCQ use. Advanced retinopathy is characterized by reduction of visual acuity and a “bull's-eye” macular lesion, which is absent in the earlier stages. Bull's eye maculopathy and/or paracentral scotoma are clinical features of HCQ retinopathy.
Macular retinal toxicity is related to the total cumulative dose. People taking 400 mg of HCQ S04 or less per day generally have lower risk of macular retinal toxicity, and the risk increases when a person takes the medication for more than 5 years or takes a cumulative dose of more than 1000 grams, and at a dose of 400 mg/day of HCQ sulfate the cumulative dose of 1000 grams is reached at 7 years of dosing (400 mg/day HCQ sulfate×365 days/year×7 years=1022 grams of HCQ sulfate) (Wolfe and Marmor, Rates and Predictors of Hydroxychloroquine Retinal Toxicity in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus, Arthritis Care and Research, 2010, 62(6):775-784; Marmor et al. (2011) Ophthalmology 118 (2): 415-22). The risk of retinal toxicity was found to be 5 times higher after 7 years of usage or 1000 grams of total exposure (Marmor et al. Arthritis Care Res. 2010; 62(6):775-84). Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors is present (Marmor et al. (2011) Ophthalmology 118 (2): 415-22). In a study of 3,995 patients with rheumatoid arthritis or systemic lupus erythematosus who were treated with HCQ sulfate, eye examinations to monitor for HCQ toxicity were obtained annually in 50.5% of patients and every 6 months in 40.4% of patients (Marmor et al. Arthritis Care Res. 2010; 62(6):775-84).
The exact mechanisms underlying HCQ-induced retinal toxicity, including retinal macular toxicity, are not clear. Studies to date have identified retinal accumulation of HCQ to levels much higher than those observed in other tissues and in the blood. In addition, HCQ binds to melanin in the retinal pigment epithelium (RPE), and such binding may contribute to or prolong HCQ's toxic effects. Some studies have demonstrated that both chloroquine and HCQ are associated with increased lipofuscin formation, a process known to be accelerated by increased lysosomal pH and intra-lysosomal oxidation during degradation of auto-/heterophagocytosed material (Sundelin et al. APMIS [Acta Pathologica, Microbiologica Immunologica Scandinavica]. 2002; 110(6):481-9). Findings suggest that chloroquine blocks attachment of autophagosomes to lysosomes, thereby resulting in the accumulation of lipofuscin and persistence chloroquine and other aminoquinolines in the retinal pigmented epithelial cells (Yoon et al, Induction of lysosomal dilatation, arrested autophagy, and cell death by chloroquine in cultured ARPE-19 cells, Invest Ophthalmol Vis Sci. 2010, 51(11):6030-7). Additionally, because melanin within the RPE has a role in neutralizing oxidative free radicals, it has been suggested that the presence of excessive levels of such free radicals may contribute to the pathogenesis of HCQ-induced retinal toxicity (Sundelin et al. APMIS. 2002; 110(6):481-9).
Retinal toxicity induced by chloroquine and HCQ is characterized by a fine mottling of the macula, arteriolar narrowing, peripheral retinal pigmentation, loss of the foveal reflex and, in advanced cases, by a depigmented macula surrounded by a pigmented ring, a finding termed “bull's-eye maculopathy” (Mecklenburg et al, Toxicol Pathol. 2007; 35(2):252-67). In the early stages of retinal toxicity, patients may notice decreased visual acuity, blurred vision, decreased color and night vision, as well as a paracentral scotoma (Mecklenburg et al, Toxicol Pathol. 2007; 35(2):252-67). HCQ retinopathy is related to the total cumulative dose and develops slowly, but can progress to a more serious loss of central and peripheral vision for which there is no known treatment (Marmor et al., Arthritis Care Res. 2010; 62(6):775-84).
Current recommendations for screening for chloroquine and HCQ retinopathy are contained in the “2011 AAO Revised Recommendations” described in Marmor et al. (Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy, Ophthalmology. 2011, 118(2):415-22). The recommendations include performing a baseline examination within the first year of patients starting hydroxychloroquine or chloroquine therapy to serve as a reference point and to rule out pre-existing maculopathy, which frequently contraindicates use of these drugs. Annual screening for eye toxicity is recommended to begin after 5 years, or sooner if there are additional risk factors including cumulative dose >1000 grams of HCQ sulfate, use of a daily dose of HCQ sulfate >400 mg/day (or >6.5 mg/kg HCQ sulfate for lean body weight for short individuals), advanced age, kidney or liver dysfunction, or retinal disease or maculopathy (Marmor et al, Opthamology. 2011, 118(2):415-22).
As described in the “2011 AAO Revised Recommendations” (Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy, Ophthalmology. 2011, 118(2):415-22), newer objective tests, such as multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF), can be more sensitive than visual field tests. It is now recommended that along with white 10-2 automated field threshold tests, at least one of these procedures be used for routine screening when available. When field tests are performed independently, even the most subtle 10-2 field changes should be taken seriously and are an indication for evaluation by objective testing. Because mfERG testing is an objective test that evaluates function, it may be used in place of visual field tests. Amsler grid testing is no longer recommended. Fundus examinations are advised for documentation, but visible bull's-eye maculopathy is a late change, and the goal of screening is to detect toxicity at an earlier stage. Further, patients should be aware of the risk of toxicity and the rationale for screening (to detect early changes and minimize visual loss, not necessarily to prevent it). The drugs should be stopped if possible when toxicity is detected or strongly suspected (Marmor et al, Ophthalmology. 2011, 118(2):415-22).
Although HCQ and other aminoquinolines have been used to treat inflammatory diseases, as discussed herein, prolonged administration of HCQ and other aminoquinolines is associated with deposition of the aminoquinoline in the retina and the development of retinal toxicity. Accordingly, there is a need for improved pharmaceutical compositions which provide anti-inflammatory activity while exhibiting less retinal accumulation and less retinal toxicity as compared to HCQ and other aminoquinolines.